Activated epidermal growth factor receptor induces integrin α2 internalization via caveolae/raft-dependent endocytic pathway

Abstract

Elevated expression or activity of the epidermal growth factor (EGF) receptor is common in ovarian cancer and is associated with poor patient prognosis. Our previous studies demonstrated that expression of the constitutively active mutant form of the EGF receptor (EGFRvIII) in ovarian cancer cells led to reduction in integrin α2 surface expression, defects in cell spreading, and disruption of focal adhesions. Inhibition of EGFRvIII catalytic activity reversed the response, suggesting that EGF receptor activation regulates integrin α2. In this study we found that EGF treatment resulted in a transient loss of integrin α2 from the cell surface. Before EGF stimulation, integrin α2 and EGF receptors were associated based on biochemical and immuno-colocalization approaches. After EGF treatment, EGF receptor and integrin α2 were internalized and segregated into different compartments. Integrin α2, but not EGF receptor, was associated with caveolin-1 and GM1 (Gal_1,3GalNAc_1,4(Neu5Ac-_2,3)Gal_1,4Glc_1, 1-ceramide) gangliosides, suggesting caveolae-mediated endocytosis. Moreover, integrin α2 was subsequently targeted to the Golgi apparatus and the endoplasmic reticulum. Together, these findings demonstrate that activated EGF receptor transiently modulates integrin α2 cell surface expression and stimulates integrin α2 trafficking via caveolae/raft-mediated endocytosis, representing a novel mechanism by which the EGF receptor may regulate integrin-mediated cell behavior. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.